Human Mixed- Lineage Leukemia, Translocated to 1 (MLLT1); A Target Enabling Package

Overexpression of MLLT1 (also known as ENL, LTG19 and YEATS1) has recently been implicated as a driver of acute myeloid leukaemia (AML)(1, 2). Its epigenetic reader domain (dubbed YEATS domain) links histone acylation to gene expression via its role in the super elongation complex (SEC) (3) and its interaction with the histone methyl transferase DOT1L. Since epigenetic readers have been shown to be tractable targets for small molecule inhibitors, we have performed a library screen using a peptide displacement assay to identify inhibitors of MLLT1 interaction with acetylated histone tails. The screen yielded a potent hit and in further characterisation with biophysical methods it displayed a sub-micromolar KD for MLLT1 and its paralog MLLT3 (Also known as AF9) with no detectable binding to two other human YEATS proteins.